Supplementary Material for: Acute Effects of 3,4-Methylenedioxymethamphetamine and Methylphenidate on Circulating Steroid Levels in Healthy Subjects

3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy') and methylphenidate are widely used psychoactive substances. MDMA primarily enhances serotonergic neurotransmission, and methylphenidate increases dopamine but has no serotonergic effects. Both drugs also increase norepinephrine, resulting in sympathomimetic properties. Here we studied the effects of MDMA and methylphenidate on 24-hour plasma steroid profiles. 16 healthy subjects (8 men, 8 women) were treated with single doses of MDMA (125 mg), methylphenidate (60 mg), MDMA + methylphenidate, and placebo on 4 separate days using a cross-over study design. Cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, aldosterone, 11-deoxycorticosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone were repeatedly measured up to 24 h using liquid chromatography-tandem mass spectroscopy. MDMA significantly increased the plasma concentrations of cortisol, corticosterone, 11-dehydrocorticosterone, and 11-deoxycorticosterone and also tended to moderately increase aldosterone levels compared with placebo. MDMA also increased the sum of cortisol + cortisone and the cortisol/cortisone ratio, consistent with an increase in glucocorticoid production. MDMA did not alter the levels of cortisone, DHEA, DHEAS, androstenedione, or testosterone. Methylphenidate did not affect any of the steroid concentrations, and it did not change the effects of MDMA on circulating steroids. In summary, the serotonin releaser MDMA has acute effects on circulating steroids. These effects are not observed after stimulation of the dopamine and norepinephrine systems with methylphenidate. The present findings support the view that serotonin rather than dopamine and norepinephrine mediates the acute pharmacologically induced stimulation of the hypothalamic-pituitary-adrenal axis in the absence of other stressors.

3,4-亚甲二氧基甲基苯丙胺（3,4-Methylenedioxymethamphetamine，MDMA，俗称“摇头丸”）与哌甲酯（methylphenidate）均为广泛使用的精神活性物质（psychoactive substances）。MDMA主要增强血清素能神经传递（serotonergic neurotransmission），哌甲酯则提升多巴胺（dopamine）水平，但不影响血清素功能。二者均可升高去甲肾上腺素（norepinephrine）水平，进而呈现拟交感神经特性（sympathomimetic properties）。本研究探究了MDMA与哌甲酯对24小时血浆类固醇谱的影响。本研究采用交叉研究设计（cross-over study design），让16名健康受试者（8名男性、8名女性）在4个独立疗程中分别接受单剂量MDMA（125 mg）、哌甲酯（60 mg）、MDMA+哌甲酯联合给药以及安慰剂（placebo）处理。研究人员采用液相色谱-串联质谱法（liquid chromatography-tandem mass spectroscopy），在24小时内重复检测了受试者血浆中的皮质醇（cortisol）、可的松（cortisone）、皮质酮（corticosterone）、11-脱氢皮质酮（11-dehydrocorticosterone）、醛固酮（aldosterone）、11-脱氧皮质酮（11-deoxycorticosterone）、脱氢表雄酮（dehydroepiandrosterone, DHEA）、硫酸脱氢表雄酮（dehydroepiandrosterone sulfate, DHEAS）、雄烯二酮（androstenedione）与睾酮（testosterone）水平。与安慰剂组相比，MDMA可显著升高血浆中皮质醇、皮质酮、11-脱氢皮质酮及11-脱氧皮质酮的浓度，且有中等程度升高醛固酮水平的趋势。MDMA还可提升皮质醇+可的松的总和以及皮质醇/可的松比值，这与糖皮质激素生成（glucocorticoid production）增加的结果一致。MDMA未改变可的松、DHEA、DHEAS、雄烯二酮或睾酮的水平。哌甲酯未对任何类固醇浓度产生影响，也未改变MDMA对循环类固醇的作用。综上，作为血清素释放剂的MDMA对循环类固醇具有急性影响，而通过哌甲酯刺激多巴胺与去甲肾上腺素系统则未观察到此类效应。本研究结果支持下述观点：在无其他应激源的情况下，介导药物急性刺激下丘脑-垂体-肾上腺轴（hypothalamic-pituitary-adrenal axis）的是血清素，而非多巴胺与去甲肾上腺素。